Dehydroascorbate accumulates in the plasma of patients with diabetes mellitus. Animals injected with dehydroascorbate or fed high ascorbate-high carbohydrate diet develop pancreatic beta-cell degranulation and hyperglycemia. We find that cellular dehydroascorbate uptake is proportional to cytosol dehydroascorbate reducing activity. Dehydroascorbate uptake by normal human PMN is competitively inhibited by glucose. Dehydroascorbate uptake by freshly isolated diabetic PMN is inversely proportional to blood glucose concentration; incubation of these cells in medium containing 5.5mM glucose causes dehydroascorbate uptake to increase slowly. We propose to: 1) Extend measurement of total ascorbate and dehydroascorbate in accessible body fluids and tissues, including amniotic fluid and cord blood, analyzing for differences among types of diabetes and correlation with blood glucose concentrations. 2) Explore possible mechanisms of dehydroascorbate accumulation in diabetics, concentrating first on the mechanisms of slowly reversible impairment of dehydroascorbate uptake and reduction in PMN from hyperglycemic donors. 3) Determine whether dehydroascorbate and derivative compounds are toxic to human cells in vitro. These studies are intended to determine whether disordered ascorbate physiology contributes to the pathogenesis of the diabetic state or of its vascular and fetal complications. If so, they might promote development of an approach to forestalling disease progression, for example, by careful control of dietary ascorbate.